Center for Gene Environment in Parkinson's Disease

描述（由申请人提供） UCLA-CGEP的目标是在了解推定环境毒物（PET）破坏的关键细胞通路的基础上，确定散发性PD的新致病机制。该小组发现高水平暴露于PET与PD之间的关联，并且在平行实验中发现PET改变可能参与疾病发病机制的特定细胞途径，泛素-蛋白酶体系统（UPS），微管聚合和醛脱氢酶（ALDH）。本项目的目标是确定UPS中断（特别是E1激活酶），微管和ALDH的候选农药在赋予多巴胺（DA）神经元的脆弱性，使用基于细胞的测定的相对重要性。我们将测试这些细胞机制单独或组合（即，多次击中）导致黑质纹状体细胞死亡，使用培养的细胞系和原代中脑神经元。该项目的第二个目标是确定黑质神经元的选择性脆弱性是否是由于，至少部分，通过测量PET暴露对DA及其代谢产物的影响，并使用病毒介导的VMAT表达改变胞质DA的DA稳态的改变。第三个目标是确定额外的农药，也能够破坏那些相同的细胞通路，改变黑质纹状体多巴胺能神经元的活力。这些研究将有助于阐明已知在长期暴露中增加PD风险的药物的作用机制。研究结果还将有助于确定哪些遗传多态性与项目4相关，筛选结果将指导进一步的农业风险因素的流行病学分析。这一假设是，确定环境因素的作用机制，增加PD的风险，将揭示参与散发性PD的病理生理过程。

DESCRIPTION (provided by applicant) The goal of the UCLA-CGEP is to identify novel pathogenic mechanisms of sporadic PD based on understanding the critical cellular pathways disrupted by Putative Environmental Toxicants (PETs). This group found associations between high levels of exposure to PETs with PD, and in parallel experiments discovered PETs alter specific cellular pathways potentially involved in disease pathogenesis, the ubiquitin-proteasome system (UPS), microtubule polymerization, and aldehyde dehydrogenase (ALDH). The goal of this project is to determine the relative importance of UPS disruption (especially E1 activating enzyme), microtubules and ALDH by candidate pesticides in conferring vulnerability to dopamine (DA) neurons using cell-based assays. We will test whether disruption of these cellular mechanisms in isolation or in combination (i.e., multiple hits) leads to nigrostriatal cell death using cell lines and primary mesencephalic neurons in culture. A secondary goal of this project is to determine whether selective vulnerability of nigral neurons is due, at least in part, to alterations in DA homeostasis by measuring the effect of PET exposure on DA and its metabolites and altering cytosolic DA using viral mediated VMAT expression. A third goal is to identify additional agricultural pesticides that are also able to disrupt those same cellular pathways shown to alter the viability of nigrostriatal dopaminergic neurons. These studies will help elucidate the mechanisms of action of agents known to increase PD risks over long periods of exposure. The results will also help determine which genetic polymorphisms associated with Project 4, and the screening results will guide further epidemiological analyses of agricultural risk factors. The hypothesis is that the determination of mechanisms of action of environmental agents that increase the risk of PD will shed light on the pathophysiological processes involved in sporadic PD.